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BJPsych Open Oct 2023Studies have shown a relationship between oestrogen and Alzheimer's disease. However, there is neither clear nor strong evidence on the use of oestrogen-only therapy in... (Review)
Review
BACKGROUND
Studies have shown a relationship between oestrogen and Alzheimer's disease. However, there is neither clear nor strong evidence on the use of oestrogen-only therapy in reducing the risk of Alzheimer's disease.
AIMS
To assess the effects of oestrogen-only therapy on reducing the risk of Alzheimer's disease.
METHOD
Inclusion criteria was determined with the PICO framework. Outcome was cognitive function measured by neuropsychological tests and strict protocols. Exclusion criteria included non-Alzheimer's dementia, progesterone-only therapy and pre-menopausal women. Searches were conducted in nine electronic healthcare databases, last searched in July 2022. Quality assessments conducted on randomised controlled trials (RCTs) were performed with the GRADE assessment, and cohort studies and case-control studies were assessed with the Newcastle-Ottawa Scale. Extracted data were used to analyse participants, interventions and outcomes.
RESULTS
Twenty-four studies satisfied the search criteria (four RCTs, nine cohort studies, 11 case-control studies). Fifteen studies showed positive associations for oestrogen-only therapy reducing the risk of Alzheimer's disease, and the remaining nine found no evidence of association.
CONCLUSIONS
Fifteen studies showed that oestrogen-only therapy effectively reduced the risk of Alzheimer's disease, whereas nine showed no correlation. Studies also investigated oestrogen-related variables such as length of oestrogen exposure, being an apolipoprotein E ε4 carrier and concomitant use of non-steroidal anti-inflammatory drugs, and their role in neuroprotection. This review was limited by the limited ranges of duration of oestrogen treatment and type of oestrogen-only therapy used. In conclusion, oestrogen-only therapy has potential for use in preventing Alzheimer's disease, although current evidence is inconclusive and requires further study.
PubMed: 37846476
DOI: 10.1192/bjo.2023.579 -
Stroke Feb 2006Apolipoprotein E genotype (APOE) is associated with cholesterol metabolism, ischemic heart disease, and cerebral amyloid angiopathy, and so may affect risk of both... (Meta-Analysis)
Meta-Analysis
Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls.
BACKGROUND AND PURPOSE
Apolipoprotein E genotype (APOE) is associated with cholesterol metabolism, ischemic heart disease, and cerebral amyloid angiopathy, and so may affect risk of both ischemic and hemorrhagic stroke.
METHODS
We comprehensively sought and identified studies of the association of apoE with ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). We did meta-analyses to assess the evidence for an association between APOE and the various pathological types and subtypes of stroke, and assessed the effects of several methodological criteria.
RESULTS
We analyzed data from 31 eligible studies (26 IS, 8 ICH, and 3 SAH) in 5961 cases and 17 965 controls. epsilon4 allele-containing (epsilon4+) genotypes were significantly associated with IS (odds ratio [OR], 1.11; 95% CI, 1.01 to 1.22) and SAH (OR, 1.42; 95% CI, 1.01 to 1.99) and nonsignificantly with ICH (OR, 1.16; 95% CI, 0.93 to 1.44), whereas epsilon2+ genotypes were associated with ICH (OR, 1.32; 95% CI, 1.01 to 1.74). Associations appeared stronger with epsilon4+ genotypes for large artery compared with other IS subtypes and for Asian compared with white populations, and with epsilon2+ genotypes for lobar compared with deep hemorrhages. However, we found no association between epsilon4+ genotypes and IS when we analyzed only larger studies (>200 cases; OR, 0.99; 95% CI, 0.88 to 1.11) or studies without control selection bias (OR, 0.99; 95% CI, 0.85 to 1.17).
CONCLUSIONS
Publication and selection biases make existing studies of APOE and stroke unreliable. Further, very large, methodologically rigorous studies are needed.
Topics: Adult; Aged; Apolipoproteins E; Cerebral Hemorrhage; Data Interpretation, Statistical; Databases, Bibliographic; Female; Genetic Predisposition to Disease; Genotype; Humans; Ischemia; Male; Middle Aged; Odds Ratio; Risk; Risk Factors; Software; Stroke; Subarachnoid Hemorrhage
PubMed: 16385096
DOI: 10.1161/01.STR.0000199065.12908.62 -
NeuroImage. Clinical 2020Diffusion magnetic resonance imaging (dMRI) is an imaging technique which probes the random motion of water molecules in tissues and has been widely applied to... (Review)
Review
Diffusion magnetic resonance imaging (dMRI) is an imaging technique which probes the random motion of water molecules in tissues and has been widely applied to investigate changes in white matter microstructure in Alzheimer's Disease. This paper aims to systematically review studies that examined the effect of Alzheimer's risk genes on white matter microstructure. We assimilated findings from 37 studies and reviewed their diffusion pre-processing and analysis methods. Most studies estimate the diffusion tensor (DT) and compare derived quantitative measures such as fractional anisotropy and mean diffusivity between groups. Those with increased AD genetic risk are associated with reduced anisotropy and increased diffusivity across the brain, most notably the temporal and frontal lobes, cingulum and corpus callosum. Structural abnormalities are most evident amongst those with established Alzheimer's Disease. Recent studies employ signal representations and analysis frameworks beyond DT MRI but show that dMRI overall lacks specificity to disease pathology. However, as the field advances, these techniques may prove useful in pre-symptomatic diagnosis or staging of Alzheimer's disease.
Topics: Alzheimer Disease; Anisotropy; Brain; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Humans; White Matter
PubMed: 32758801
DOI: 10.1016/j.nicl.2020.102359 -
Journal of Alzheimer's Disease : JAD Aug 2007MCI is a nosological entity proposed as an intermediate state between normal aging and dementia. The syndrome can be divided into two broad subtypes: amnestic MCI (aMCI)... (Review)
Review
MCI is a nosological entity proposed as an intermediate state between normal aging and dementia. The syndrome can be divided into two broad subtypes: amnestic MCI (aMCI) characterized by reduced memory, and non-amnestic MCI (naMCI) in which other cognitive functions rather than memory are mostly impaired. aMCI seems to represent an early stage of AD, while the outcomes of the naMCI subtypes appear more heterogeneous--including vascular dementia, frontotemporal dementia or dementia with Lewy bodies--but this aspect is still under debate. MCI in fact represents a condition with multiple sources of heterogeneity, including clinical presentation, etiology, and prognosis. To improve classification and prognosis, there is a need for more sensitive instruments specifically developed for MCI as well as for more reliable methods to determine its progression or improvement. Current clinical criteria for MCI should be updated to include restriction in complex ADL; also the diagnostic and prognostic role of behavioral symptoms and motor dysfunctions should be better defined. A multidisciplinary diagnostic approach including biological and neuroimaging techniques may probably represent the best option to predict the conversion from MCI to dementia. In this review we discuss the most recent aspects related to the epidemiological, clinical, neuropathological, neuroimaging, biochemical and therapeutic aspects of MCI, with specific attention to possible markers of conversion to dementia.
Topics: Alzheimer Disease; Apolipoprotein E4; Brain; Cognition Disorders; Dementia, Vascular; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Memory Disorders; Neuropsychological Tests; Radiopharmaceuticals; Risk Factors; Severity of Illness Index
PubMed: 17851192
DOI: 10.3233/jad-2007-12104 -
Acta Neuropathologica Communications Jan 2022The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain...
Association between single moderate to severe traumatic brain injury and long-term tauopathy in humans and preclinical animal models: a systematic narrative review of the literature.
BACKGROUND
The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain controversial. Some studies suggest that moderate to severe TBI is sufficient to promote tau pathology; however, others suggest that it is simply a consequence of aging. We therefore conducted a systematic narrative review of the literature addressing whether a single moderate to severe head injury leads to long-term development of tauopathy in both humans and animal models.
METHODS
Studies considered for inclusion in this review assessed a single moderate to severe TBI, assessed tau pathology at long-term timepoints post-injury, comprised experimental or observational studies, and were peer-reviewed and published in English. Databases searched included: PUBMED, NCBI-PMC, EMBASE, Web of Science, Academic Search Premiere, and APA Psychnet. Search results were uploaded to Covidence®, duplicates were removed, and articles underwent an abstract and full-text screening process. Data were then extracted and articles assessed for risk of bias.
FINDINGS
Of 4,150 studies screened, 26 were eligible for inclusion, of which 17 were human studies, 8 were preclinical animal studies, and 1 included both human and preclinical animal studies. Most studies had low to moderate risk of bias. Most human and animal studies (n = 12 and 9, respectively) suggested that a single moderate to severe TBI resulted in greater development of long-term tauopathy compared to no history of head injury. This conclusion should be interpreted with caution, however, due to several limitations: small sample sizes; inconsistencies in controlling for confounding factors that may have affected tau pathology (e.g., family history of dementia or neurological illnesses, apolipoprotein E genotype, etc.), inclusion of mostly males, and variation in reporting injury parameters.
INTERPRETATION
Results indicate that a single moderate to severe TBI leads to greater chronic development of tauopathy compared to no history of head injury. This implies that tau pathology induced may not be transient, but can progressively develop over time in both humans and animal models. Targeting these tau changes for therapeutic intervention should be further explored to elucidate if disease progression can be reversed or mitigated.
Topics: Animals; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Humans; Tauopathies
PubMed: 35101132
DOI: 10.1186/s40478-022-01311-0 -
Alzheimer's Research & Therapy Nov 2020Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer's disease (AD). While researchers have... (Review)
Review
Possession of the ε4 allele of apolipoprotein E (APOE) is the primary genetic risk factor for the sporadic form of Alzheimer's disease (AD). While researchers have extensively characterized the impact that APOE ε4 (APOE4) has on the susceptibility of AD, far fewer studies have investigated the phenotypic differences of patients with AD who are APOE4 carriers vs. those who are non-carriers. In order to understand these differences, we performed a qualitative systematic literature review of the reported cognitive and pathological differences between APOE4-positive (APOE4+) vs. APOE4-negative (APOE4-) AD patients. The studies performed on this topic to date suggest that APOE4 is not only an important mediator of AD susceptibility, but that it likely confers specific phenotypic heterogeneity in AD presentation, as well. Specifically, APOE4+ AD patients appear to possess more tau accumulation and brain atrophy in the medial temporal lobe, resulting in greater memory impairment, compared to APOE4- AD patients. On the other hand, APOE4- AD patients appear to possess more tau accumulation and brain atrophy in the frontal and parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. Although more work is necessary to validate and interrogate these findings, these initial observations of pathological and cognitive heterogeneity between APOE4+ vs. APOE4- AD patients suggest that there is a fundamental divergence in AD manifestation related to APOE genotype, which may have important implications in regard to the therapeutic treatment of these two patient populations.
Topics: Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Atrophy; Cognition; Humans
PubMed: 33148345
DOI: 10.1186/s13195-020-00712-4 -
International Journal of Environmental... Jul 2021Physical activity (PA) reduces the risk of cognitive decline (CD) in the general population. However, little is known about whether the presence of the apolipoprotein E... (Review)
Review
Physical activity (PA) reduces the risk of cognitive decline (CD) in the general population. However, little is known about whether the presence of the apolipoprotein E epsilon 4 allele () could modify this beneficial effect. The aim of this systematic review was to analyze and synthetize the scientific evidence related to PA levels and CD risk in cognitively healthy carriers. Four electronic databases were analyzed. Only original articles with longitudinal study design were selected to analyze the relationship between PA and CD in carriers. Five studies were included in the systematic review. All studies except one stated that PA is a protective factor against CD in carriers. Moreover, partial support was found for the hypothesis that a greater amount and intensity of PA are more beneficial in CD prevention. The results support the idea that PA is a protective factor against CD in carriers. Nevertheless, it would be necessary to carry out further studies that would allow these findings to be contrasted.
Topics: Alleles; Apolipoprotein E4; Apolipoproteins E; Cognitive Dysfunction; Exercise; Genotype; Humans; Longitudinal Studies
PubMed: 34299687
DOI: 10.3390/ijerph18147238 -
BioMed Research International 2019The apolipoprotein E knockout (ApoE -/-) mouse model is well established for the study of terpenoids in the prevention of atherosclerosis. Studies investigating the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The apolipoprotein E knockout (ApoE -/-) mouse model is well established for the study of terpenoids in the prevention of atherosclerosis. Studies investigating the clinical benefit of terpenoids in humans are scarce. This systematic review and meta-analysis evaluated the effects of terpenoid administration on atherosclerotic lesion area in ApoE -/- mice.
METHODS
A comprehensive literature search using PubMed, Embase, and the Cochrane Library databases was performed to identify studies that assessed the effects of terpenoids on atherosclerosis in ApoE -/- mice. The primary outcome was atherosclerotic lesion area, and study quality was estimated using SYRCLE's risk of bias tool.
RESULTS
The meta-analysis included 25 studies. Overall, terpenoids significantly reduced atherosclerotic lesion area when compared to vehicle control (<0.00001; SMD: -0.55; 95% CI: -0.72, -0.39). In terpenoid type and dose subgroup analyses, sesquiterpenoid (=0.002; SMD -0.93; 95% CI: -1.52, -0.34), diterpenoid (=0.01; SMD: -0.30; 95% CI: -0.54, -0.06), triterpenoid (<0.00001; SMD: -0.66; 95% CI: -0.94, -0.39), tetraterpenoid (<0.0001; SMD: -1.81; 95% CI: -2.70, -0.91), low dose (=0.0001; SMD: -0.51; 95% CI: -0.76, -0.25), medium dose (0.0001; SMD: -0.48; 95% CI: -0.72, -0.24), and high dose (=0.002; SMD: -1.07; 95% CI: -1.74, -0.40) significantly decreased atherosclerotic lesion area when compared to vehicle control. PROSPERO register number is CRD42019121176.
CONCLUSION
Sesquiterpenoid, diterpenoid, triterpenoid, and tetraterpenoid have potential as antiatherosclerotic agents with a wide range of doses. This systematic review provides a reference for research programs aimed at the development of terpenoid-based clinical drugs.
Topics: Animals; Aortic Diseases; Atherosclerosis; Disease Models, Animal; Mice; Mice, Knockout, ApoE; PubMed; Terpenes
PubMed: 31392210
DOI: 10.1155/2019/2931831 -
Cardiovascular Therapeutics Oct 2016Warfarin is the most extensively used coumarin anticoagulant. It has been shown that the anticoagulant effect of warfarin is associated with genetic variation.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Warfarin is the most extensively used coumarin anticoagulant. It has been shown that the anticoagulant effect of warfarin is associated with genetic variation. Apolipoprotein E (ApoE) is a possible candidate to influence the maintenance dose of warfarin. ApoE affects the vitamin K cycle by mediating the uptake of vitamin K into the liver. The vitamin K cycle is the drug target of warfarin. However, the association between genetic variants of the APOE gene and warfarin dose requirement is still controversial.
METHODS
Revman 5.3 software was used to analyze the relationship between APOE genotypes and warfarin dose requirements.
RESULTS
In our meta-analysis, the E2/E2 genotype was significantly associated with warfarin dose. E2/E2 patients required 12% (P = 0.0002) lower mean daily warfarin dose than E3/E3 carriers. In addition, subgroup analysis showed that Asians with the E4/E4 genotype tended to need lower warfarin maintenance doses, while the African American E4/E4 carriers needed slightly higher doses than E3/E3 carriers; however, these subgroups were very small.
CONCLUSION
This is the first meta-analysis of the association between APOE genotypes and warfarin dose. APOE E2/E2 might be one of the factors affecting warfarin dose requirements. The effect of APOE may vary between ethnicities.
Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Apolipoproteins E; Blood Coagulation; Chi-Square Distribution; Drug Dosage Calculations; Ethnicity; Female; Gene Frequency; Genotype; Humans; International Normalized Ratio; Male; Middle Aged; Pharmacogenetics; Pharmacogenomic Variants; Phenotype; Polymorphism, Genetic; Warfarin
PubMed: 27062534
DOI: 10.1111/1755-5922.12186 -
Alzheimer Disease and Associated... 2009The purpose of this study was to conduct a systematic review of the literature of cardiovascular factors pertaining to incident Alzheimer disease (AD). (Review)
Review
OBJECTIVE
The purpose of this study was to conduct a systematic review of the literature of cardiovascular factors pertaining to incident Alzheimer disease (AD).
METHODS
A systematic literature review was conducted of all studies of cardiovascular risk factors for incident AD listed in PubMed in English from 2000 to 2007. Risk factors included hypertension, diabetes, exercise, alcohol intake, smoking, B complex vitamins, homocysteine, stroke, atrial fibrillation, apolipoprotein E (APOE), lipids, and diet. Inclusion criteria consisted of diagnoses of incident AD and longitudinal studies with cohorts of 500 or more.
RESULTS
Individual clinically defined risk factors such as hypertension and diabetes were not significantly associated with increased risk for AD. The strength of the association for hypertension could be considerably strengthened by changing criteria such as midlife measurements or using higher cutoffs for systolic blood pressure. APOE epsilon4 was the most consistent risk factor. Interactions between risk factors modify risk particularly for hypertension and diabetes. Interactions modifying risk were also found for exercise and physical function, APOE epsilon4, diabetes, and cholesterol.
CONCLUSIONS
In this review, the evidence that single clinically defined cardiovascular risk factors are significantly associated with incident AD is inconsistent at best. The strength of the association of cardiovascular risk factors and AD can be influenced greatly by changing the parameters of measurement of risk factors and by identifying interactions between the factors.
Topics: Alzheimer Disease; Cardiovascular Diseases; Humans; Risk Factors
PubMed: 18703981
DOI: 10.1097/WAD.0b013e318187541c